Overview of Vulnerable Plaque

An overview of the characteristics, detection methods, and response to treatment of vulnerable plaque in the carotids

By Emile R. Mohler III, MD
 

Vulnerable plaque is a concept that describes atherosclerotic plaques that are prone to precipitate acute thrombotic occlusion of arteries. The vulnerability develops due to pathophysiologic components, as well as environmental and genetic influences. One new concept is that not only are there vulnerable plaques, there are actually vulnerable patients. The patient's risk factors (ie, continued smoking, untreated lipids, uncontrolled diabetes) are very important to plaque stability, in addition to the plaque components. A vulnerable patient is one who has risk factors that are treatable, but may not be under control. It does not necessarily mean that controlling all of the risk factors will prevent a cardiovascular event, but it does mean that there are vulnerable aspects of the patient that should be addressed. New imaging techniques are emerging that will likely identify more vulnerable patients. This review will focus on the plaque components that increase carotid atherosclerotic plaque instability and novel imaging modalities to identify the unstable plaque.

UNSTABLE ATHEROSCLEROTIC PLAQUE PRESENTATION
Atherosclerosis is a diffuse process with underlying chronic inflammation that involves vascular, metabolic, and immune systems that may lead to plaque vulnerability (Table 1). When evaluating a patient, it is difficult with just a clinical history and physical examination to determine the plaque's current stage. There are several types of dangerous plaques believed to cause a cardiovascular event. (1) Plaque rupture is when the constituents of the plaque are exuded into the circulation, expressing tissue factor, resulting in thrombus formation in that region. (2) A thrombus can occur on a de-endothelialized (ulcerated), but otherwise intact, plaque. This may lead to vessel occlusion and hemodynamic compromise due to vessel occlusion and may also occur without a plaque rupture. (3) It is also possible to have a thrombus occur on the nidus of a calcified nodule that projects into the circulation and may act as a "lightning rod" for thrombus formation, which might then embolize and cause a cerebrovascular event. (4) Another possibility is when a thrombus forms within the plaque. This intraplaque hemorrhage is usually asymptomatic because it is walled off by the plaque cap (ie, there is no eruption of the plaque). However, this may lead to further carotid stenosis and hemodynamic compromise.

ATHEROSCLEROTIC PLAQUE CHARACTERISTICS
Several different characteristics of plaque have been identified and correlated with risk of a cardiovascular event. Traditionally, a thin fibrous cap with inflammation is more vulnerable to rupture than those with a thick cap. The ratio of calcification to lipid content may also affect plaque stability. We studied carotid atherosclerotic calcification and found that extracranial carotid calcified plaques are significantly less likely to be symptomatic than more noncalcified, lipid-filled plaques.1 Furthermore, data suggest an inverse relationship between the degree of plaque calcification and macrophage infiltration in carotid stenosis, indicating that the lipid to calcium ratio is important.

The prevalence of plaque ulceration is comparable for both the ipsilateral symptomatic (ie, the carotid on the side the symptoms occur) and the contralateral symptomatic groups. In contrast, emboli are most common in plaques with both ipsilateral symptoms and ulceration. Some data suggest that if ulceration of the plaque exists, that particular cerebrovascular territory is vulnerable.

INFLAMMATORY FACTORS THAT AFFECT PLAQUE VULNERABILITY
Thrombotically active carotid plaques have increased amounts of inflammatory infiltrates. In a study by Spagnoli et al, extracranial thrombotically active carotid plaques were evaluated as a risk factor for stroke.2 They reported that high inflammatory infiltrate was found in 71 of 96 patients (74%), but ipsilateral major stroke compared with 32 of 91 patients with a transient ischemic attack, or 12 of 18 patients (14%) who were asymptomatic. On the contrary, carotid calcification with relatively less cholesterol content in the plaque portends a better prognosis with fewer ischemic strokes.1,3

The endothelium does not normally express inflammatory signals (adhesion molecules), but these are found on dysfunctional endothelium, especially in regions of atherosclerotic plaques. It is plausible that increased expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) may be a factor in converting an asymptomatic plaque to a symptomatic plaque, as noted in one study.4 However, another study in which adhesion molecule expression was compared in symptomatic and asymptomatic carotid stenosis did not find a significant difference between the two groups.5

Matrix Metalloproteinases
Matrix metalloproteinases (MMPs) in carotid atheroma are thought to have a significant role in plaque stability.6 Studies indicate a link between MMPs and plaque stability, such as MMP-1 and MMP-12.7 One study found that the MMP-12 transcript levels were significantly increased in ruptured plaques compared with lesions without cap disruption.8 One other source of MMP production is via T-cell stimulation of macrophages. T cells stimulate a cell surface on the macrophage called CD40 ligand that then induces MMP release. The MMPs can also entice smooth muscle cells to go through apoptosis via production of interleukin 1. Cap thinning may then result due to reduced numbers of smooth muscle cells.

High-Sensitivity C-Reactive Protein
High-sensitivity C-reactive protein (hsCRP) has been investigated as a marker for cardiovascular risk in the carotids, but has not yet been found to be a significant risk factor for stroke.9 However, one report found that by measuring hsCRP and then removing the plaque via carotid endarterectomy, the hsCRP value decreases.10 To date, there are no published reports as to whether carotid stent placement reduces hsCRP levels.

Shear Stress Plaque Instability
Shear is the friction that the blood flow exerts across an area and is measured as either normal, low, or high. Patients who have low wall sheer can develop arterial damage and plaque instability due to several factors: (1) increased fluid resonance time, (2) increased platelet and macrophage adhesion to the arterial wall, and (3) modulation of platelet-derived growth factor and transforming growth factor beta.11 Thus, blood rheology affects the stability of carotid plaques.12

Neovascularization
The vasovasorum, a microvascular network that supplies nutrition from the adventitial layer to the vascular lining, has been implicated as supportive to atherosclerotic plaque growth. Atherosclerotic plaques have neovascular structures that likely provide nutritional support for vessel wall thickening. Thus, it has been postulated that plaque neovascularization may contribute to plaque instability.13 Some plaques will undergo neovascularization and maybe even more extensive adventitial vessels surrounding the formation of plaque, which may predispose the plaque to vulnerability.

Genetic Factors
The discovery of the human genome has enabled genetic studies of atherosclerotic plaques. For example, one study reported increased numbers of genetic polymorphisms for proinflammatory genes such as hsCRP, interleukin 6, monocyte chemoattractant protein 1, ICAM-1, and E-selectin increase the odds of stroke.14 The interaction of genes and atherosclerotic disease are only now beginning to be understood and will likely yield new patient-specific assessment and treatment.

HOW VULNERABLE PLAQUES RESPOND TO INTERVENTION
If a vulnerable plaque exists during a carotid procedure, increased microdebris and emboli may occur. Embolic protection is now understood as essential when doing percutaneous intervention on a carotid plaque. A report by Hellings concluded that microembolization is an important issue in carotid artery stenting.15 During different phases of the stenting process, numerous microemboli are dislodged from atherosclerotic plaque. During the procedure, embolization can be measured by transcranial Doppler monitoring. Evidence has accumulated that unstable vulnerable plaques are associated with increased microembolization during carotid interventions, suggesting that plaques should possibly be imaged before the procedure to determine their vulnerability. Further information is needed to determine if and how ultrasound imaging should be performed during carotid interventions.

IMAGING AND DETECTION TECHNIQUES
Conventional Imaging
Several conventional imaging techniques have been modified to evaluate plaque status, including B-mode ultrasound, high-resolution MRI, spiral CT, and PET (Table 2).

Ultrasound (US) imaging of carotid plaques typically involves use of a high-frequency transducer (8 mHZ) with B-mode imaging. Prospective studies with US, several of them Scandinavian, found that if an echogenic plaque exists (one that is heavily calcified), there is a lesser risk of stroke than if a lipid-filled, echolucent plaque existed.3 Intravascular US has also been explored, but it is not routinely used because of its invasive nature. Other investigators have looked at carotid intimal medial thickness (IMT) as a marker for vulnerability to future cardiovascular events. Carotid IMT, especially those with >1-mm thickness, is now a well-recognized risk factor for atherosclerotic disease development in both carotid and coronary arteries.16

High-resolution MRI is emerging as a modality that allows for quantization of the size of the atherosclerotic lesion and even lesion composition (ie, whether it is a vulnerable plaque). MRI does not easily depict calcium, whereas CT scans do. Generally, if a US shows an ulcerated plaque, confirmation can be done using MRI. In the future, it may be possible to use MRI tools that would allow patients to be stratified into different categories based on presence of a vulnerable plaque, even if the patients are asymptomatic. However, at present, there is no commercially available MR program that characterizes carotid plaque components.

CT scanning with or without x-ray contrast dye can identify lipid content of plaques, which may in the future allow for plaque stratification as to stable or unstable. A problem with CT scans is that calcium in the plaque can create shadowing, making it difficult to determine the degree of stenosis and plaque components.

Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning is a highly sensitive imaging modality that is being tested for detection of inflammation in atherosclerotic plaque. Studies indicate increased FDG tracer uptake in regions of atherosclerosis.17,18 This vascular uptake might be explained by smooth muscle metabolism in the media, subendothelial smooth muscle proliferation from senescence, and the presence of macrophages within the atherosclerotic plaque.

MOLECULAR IMAGING
Conventional imaging techniques rely on heterogeneous anatomical structures to evaluate plaques but have limited capability in discerning molecular structures. Several novel imaging techniques are under development to detect vulnerable plaques, including temperature-sensitive probes and optical devices. One technique involves imaging with fiber optics (Xplora PD, Medeikon Corporation, Ewing, NJ). This intra-arterial device uses a combination of optical techniques to measure tissue properties in the wall, with depth resolution on the order of 10 to 15 ┬Ám. Ultrasound and fluorescent probes are being tested on atherosclerotic plaques and have the potential of offering enhanced spatial and temporal resolution.

The emerging field of molecular imaging is aimed at the study of pathologic molecular and cellular mechanisms that are ongoing in the plaque (Table 3). One strategy has been to develop molecular tags aimed at specific pathologic components of the plaque. For example, for thrombus, fibrin-targeted nanoparticles have been created (nanomedicine).19 Neovascularization in plaque is another target and involves aVb3 integrin-targeted paramagnetic nanoparticles.20 Potential therapies aimed at treatment of atherosclerotic plaque are currently being tested using this nanomedicine approach.21

RESPONSE OF VULNERABLE PLAQUES TO PHARMACOLOGICAL INTERVENTION
Studies indicate that some drugs approved by the FDA to reduce cardiovascular events work in part via plaque stabilization. For example, HMG CoA reductase inhibitors (statins) are thought to stabilize plaques by inhibiting production of MMPs from macrophages. Statins may also have other pleotrophic effects on inflammatory cells.22 One hypothesis is that statins not only reduce LDL cholesterol, but may actually stabilize plaque by interfering with this inflammatory response. A definitive answer regarding the pleotrophic action of statins on plaque stability is difficult to determine because the LDL-lowering and anti-inflammatory effects cannot be separated.

Drugs used for other purposes, such as reduction of glucose levels, may also promote plaque stability. The peroxisome proliferator-activated receptor (PPAR) gamma agonists ameliorate the effect of systemic metabolic risk factors. The PPAR gamma agonist rosiglitazone demonstrated vascular protective effects in hypercholesterolemic animals.23 The PPAR gamma agonists probably have an endothelial protective effect on the vascular surface via reduced leukocyte accumulation.

Cilostazol is approved by the FDA for treatment of claudication due to peripheral arterial disease;24 however, it may also benefit the cerebrovascular system. In a study of patients with acute symptomatic stenosis in the middle cerebral artery, 135 patients were randomized to receive either cilostazol or placebo on the background of aspirin therapy with the primary outcome of progression of symptomatic intra-arterial stenosis.25 In the cilostazol group, three of 45 symptomatic patients had progressed versus 11 who had regressed. In the placebo group, 15 symptomatic patients had progressed versus eight who regressed, which was statistically significant. Thus, it is possible that cilostazol might have a beneficial effect on cerebrovascular atherosclerosis.

There are therapies under study, such as the MMP inhibitors, that may stabilize carotid plaques.26 These agents may prevent major collagen degradation and, in effect, reduce cap thinning and risk of plaque rupture or erosion.

CONCLUSION
Unstable plaques are problematic because once they exist, it is difficult to determine if they should be treated differently than stable plaques. If the patient is asymptomatic, should we be more aggressive with unstable plaques? More studies need to be conducted that evaluate interventions in patients with unstable plaques. We are nearing the point when it will be possible to identify the unstable plaques using modified conventional and novel molecular imaging techniques. The next step is to gather more information to determine what to do about the identified unstable plaque. Do we just treat with medication, or do we intervene, or do both? It is, however, clear that we cannot forget the vulnerable patient when focusing on the vulnerable plaque because risk factor evaluation is needed to maximize patient survival and quality of life.

Emile R. Mohler III, MD, is Director of Vascular Medicine at University of Pennsylvania Health System, Philadelphia, Pennsylvania. He has disclosed that he is a paid consultant to Medeikon Corporation. Dr. Mohler may be reached at emile.mohler@uphs.upenn.edu.

 

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